Relevance of tumour necrosis factor-alpha for the inflammatory and nociceptive responses evoked by carrageenan in the mouse paw.

1. The present study evaluated the participation of tumour necrosis factor-alpha (TNF-alpha) in the inflammatory and nociceptive responses evoked by carrageenan in the mouse paw. 2. The intraplantar injection of carrageenan (300 microg paw-1) induced a marked and biphasic paw oedema formation (peaks at 6 and 72 h), which was accompanied by a long-lasting mechanical allodynia (that remained elevated for up to 72 h) and a significant increase of myeloperoxidase (MPO) activity (peak at 6 h) in both Swiss and C57/BL6 mice. 3. The paw oedema, the elevation of MPO activity and to a lesser extent the mechanical allodynia elicited by carrageenan were found to be significantly reduced in TNF-alpha p55 receptor knockout mice. 4. Of interest, the systemic administration of an anti-TNF-alpha antibody produced a significant inhibition of paw oedema, mechanical allodynia and MPO activity. A noteworthy decrease in inflammatory and nociceptive responses caused by carrageenan was also observed when mice were previously treated with the preferential inhibitor of TNF-alpha synthesis, thalidomide. 5. The present results clearly indicate that the proinflammatory cytokine TNF-alpha plays a critical role in the oedema formation, as well as in the mechanical allodynia and the neutrophil migration, following carrageenan administration into the mouse paw. Intraplantar injection of carrageenan in mice could constitute a useful model for assessment of the in vivo effects of potential inhibitors of TNF-alpha-related pathways.

Assessment of TNFalpha contribution to the functional up-regulation of kinin B(1) receptors in the mouse paw after treatment with LPS.

It has been widely demonstrated that LPS is able to induce kinin B(1) receptor up-regulation throughout several models of inflammation. Using an in-vivo system in which LPS was administered systemically, we assessed the participation of the pro-inflammatory cytokine TNFalpha in the functional up-regulation of B(1) receptors in the mouse paw. Systemic treatment with LPS (10 microg/animal, i.v. 24 h before) resulted in a marked increase (about 5-fold) in the mouse paw edema induced by the selective B(1) receptor agonist des-Arg(9)-BK (50 nmol/paw) in both Swiss and C57/BL6 mice. The up-regulation of des-Arg(9)-BK-caused edema following LPS treatment was found to be greatly diminished in TNFalpha p55(-/-) receptor knockout mice. In addition, the paw edema evoked by des-Arg(9)-BK was significantly reduced when mice received the anti-TNFalpha antibody (100 [corrected] microg/kg, i.v.) 5 min before the LPS treatment. A similar inhibition of B(1) receptor-mediated paw edema was observed when mice were treated with thalidomide (30 mg/kg, s.c.) [corrected] a drug known for reducing TNFalpha synthesis, 5 min prior to LPS administration. ELISA experiment [corrected] revealed that TNFalpha serum levels were maximal at 1 h following LPS systemic treatment. Taken together, the present results suggest that the early production of the pro-inflammatory cytokine TNFalpha is probably responsible for driving the sequence of events involved in the functional up-regulation of B(1) receptors in the mouse paw.